10-110014755-A-G

Variant names:

• chr10-110014755-A-G
• rs7099604
• NM_016824.5:c.-30+6456A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_016824.5(ADD3):​c.-30+6456A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.28 in 150,840 control chromosomes in the GnomAD database, including 8,809 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.28 (8809 hom., cov: 32)
• Consequence: ADD3 NM_016824.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.75
• Publications: 7 publications found

Genes affected

ADD3 (HGNC:245): (adducin 3) Adducins are heteromeric proteins composed of different subunits referred to as adducin alpha, beta and gamma. The three subunits are encoded by distinct genes and belong to a family of membrane skeletal proteins involved in the assembly of spectrin-actin network in erythrocytes and at sites of cell-cell contact in epithelial tissues. While adducins alpha and gamma are ubiquitously expressed, the expression of adducin beta is restricted to brain and hematopoietic tissues. Adducin, originally purified from human erythrocytes, was found to be a heterodimer of adducins alpha and beta. Polymorphisms resulting in amino acid substitutions in these two subunits have been associated with the regulation of blood pressure in an animal model of hypertension. Heterodimers consisting of alpha and gamma subunits have also been described. Structurally, each subunit is comprised of two distinct domains. The amino-terminal region is protease resistant and globular in shape, while the carboxy-terminal region is protease sensitive. The latter contains multiple phosphorylation sites for protein kinase C, the binding site for calmodulin, and is required for association with spectrin and actin. Alternatively spliced adducin gamma transcripts encoding different isoforms have been described. The functions of the different isoforms are not known. [provided by RefSeq, Jul 2008]

ADD3 Gene-Disease associations (from GenCC):

• cerebral palsy, spastic quadriplegic, 3

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• complex neurodevelopmental disorder with motor features

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• spastic quadriplegic cerebral palsy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.571 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADD3	NM_016824.5	c.-30+6456A>G		intron_variant	Intron 1 of 14	ENST00000356080.9	NP_058432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADD3	ENST00000356080.9	c.-30+6456A>G		intron_variant	Intron 1 of 14	1	NM_016824.5	ENSP00000348381.4

Frequencies

GnomAD3 genomes AF: 0.279 AC: 42086 AN: 150716 Hom.: 8785 Cov.: 32

Gnomad AFR AF: 0.577

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.170

Gnomad ASJ AF: 0.166

Gnomad EAS AF: 0.415

Gnomad SAS AF: 0.395

Gnomad FIN AF: 0.0860

Gnomad MID AF: 0.210

Gnomad NFE AF: 0.143

Gnomad OTH AF: 0.260

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.280 AC: 42166 AN: 150840 Hom.: 8809 Cov.: 32 AF XY: 0.279 AC XY: 20487 AN XY: 73562

African (AFR) AF: 0.578 AC: 23812 AN: 41228

American (AMR) AF: 0.170 AC: 2568 AN: 15082

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 576 AN: 3468

East Asian (EAS) AF: 0.415 AC: 2093 AN: 5044

South Asian (SAS) AF: 0.394 AC: 1871 AN: 4752

European-Finnish (FIN) AF: 0.0860 AC: 891 AN: 10362

Middle Eastern (MID) AF: 0.222 AC: 60 AN: 270

European-Non Finnish (NFE) AF: 0.143 AC: 9646 AN: 67646

Other (OTH) AF: 0.263 AC: 546 AN: 2078

Alfa AF: 0.209 Hom.: 697

Bravo AF: 0.293

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.14
DANN	Benign	0.18
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs7099604; hg19: chr10-111774513;